Download Introduction

Introduction
Worldwide cancer is the second most common cause of death next only to cardiovascular disease. Amongst the
type of cancers, breast cancer is the most common malignant tumor constituting 21% of all tumors [1]. It is the
most common cancer of women in urban India [2]. According to urban cancer registry in India it accounts for
around 30% of all cancers in females [3]. In India breast cancer has overtaken cervical cancer in many regions,
which was the most frequent type of cancer a decade ago [4].
Conventionally many risk factors have been associated with breast cancer, but age is the single most important
risk factor [5]. Other factors include lower age at menarche(<12 yrs.), higher age for menopause(>55yrs.),
higher age for first full term pregnancy, lesser duration of breast-feeding, benign breast disease, genetic factors,
obesity, environmental and hormonal factor [6], however in 50% of women the risk factors are not detected [7].
Breast cancer is a clonal disease. It may occur due to germline, genetic or acquired mutation in PTEN, BRCA-1,
BRCA-2 and p53 genes [6].
Normal breast tissue is estrogen dependent. Primary or metastatic breast cancer may retain this phenotype. It is
one of the hormone dependant tumors, the hormones predominantly secreted by ovaries. That is why, women
without functioning ovaries and not receiving estrogen supplementation have lesser chances of developing it and
those with cancer may respond to endocrine therapy, if found positive for hormone receptors [6].
Immunohistochemistry has diagnostic and theranostics role in cases of breast cancer. Hormone receptors are
routinely measured as it could impact treatment decisions. Gone are the days when patients were treated
empirically with tamoxifen. Estrogen receptors positive breast cancers respond to hormonal therapy in 30%
cases, both Estrogen and progesterone receptor positivity increases the likelihood of response in 70% cases ,
whereas if both are negative the response rate is reduced to just 5%. In hormonal therapy even PR positivity
implies a functioning ER pathway [8].
Clinical trials have also shown that the survival advantage for women with hormone receptor-positive tumors
is further enhanced by treatment with adjuvant hormonal and/or chemotherapeutic regimens [9]. Human
epidermal receptor-2/neu (HER-2/neu) gene amplification occurs in 20-30% of breast cancers and it is
associated with poor prognosis, lower response to hormone therapy and chemotherapy.
The present study was planned keeping in mind to establish the hormone receptor status pattern and it's
correlation with age and sex in a north Indian population of patients presenting in a tertiary care cancer hospital
of Bihar.
Materials and Methods
Study Design
The study was carried out in Mahavir Cancer Sansthan and Research Centre which is a tertiary care cancer
hospital of Bihar. A total of 1446 cases of epithelial malignancy of breast were included, of which 1423 were
women and 23 were male. Rare malignancies presenting in breast like sarcomas and lymphomas were not
included. The cases were selected randomly, who presented in our hospital between August 2009 to March
2016.The identity of the cases were kept secret and ethical permission was taken from Institutional Ethical
Committee, Mahavir Cancer Sansthan And Research Centre.
Methodology for immunohistochemistry
All the cases were immunohistochemically evaluated for estrogen and progesterone hormone receptor status,
(ER and PR), expression using standard HRP Detection system method. Pressure cooking/ microwave method
was used for antigen retrieval. Adequate tissue fixation in 10% neutral buffered formalin for 6-48 h was
ensured. Paraffin sections (3-4 μm thick) with maximum invasive tumor component were selected for IHC. The
antibodies used for ER and PR were monoclonal rabbit anti-Human Estrogen Receptor, BIOGENEX (Clone ID5
and EP1; prediluted) and monoclonal, mouse anti-Human Progesterone Receptor, BIOGENEX (Clone PR 88;
prediluted) respectively. The scores for ER and PR were calculated using the Allred Scoring method.
All the tests were interpreted with negative and positive controls. Staining of the nuclei of the normal ductal
epithelium was used as the internal control for ER and PR staining while interpreting the slides.
ER or PR was considered positive if finding of more than 1% tumor cell nuclei are immunoreactive. Negative
for ER or PR if finding of less than 1% of tumor cell nuclei are immunoreactive
Statistical Analysis:
Analysis was done by using statistical software Graphpad Prism and data was expressed as mean ± SEM and
percentages.
Results
Out of the 1446 cases of breast cancer that were studied, 1423 were women and 23 were men. The ages of the
study subjects ranged from 18 to 83 years. The median age was 50 years. Mean ± Standard Error Of Mean
(SEM) age of male breast cancer patients is 60.96 ± 2.46 years Whereas the Mean ± SEM age of female breast
cancer patients is 47.56 ± 0.29 years. Total number of ER and PR positive female patients is 505 whereas ER
and PR positive male patients is 19 the number of ER positive and PR negative female patients is 123.0 whereas
3.0 male patients. There was no male patient in the category of ER negative and PR positive tumor.
In comparison of number of overall patients with ER positive and PR positive tumors with ER negative and PR
negative tumors is 36.24% as compared to 45.23% (Figure - 1).
Patients of less than 35 years of breast carcinoma are considered very young and when these patients were
compared to higher age group with regards of ER positive and PR positive number of tumors is 5.27% as
compared to 30.22%. In comparison of same group of patients the number of ER positive and PR negative
patients, is 1.12% and 7.52% respectively. When ER negative and PR positive number of tumors was compared
in the above mentioned population groups is 1.34% in patients of less than 35 years of age of breast carcinoma
as compared to 8.64% in higher age group. On analyzing ER negative and PR negative tumors, it was found that
in below 35 yrs of population of carcinoma breast this pattern of non expression of hormone receptors were
relatively and significantly higher and for this population is 7.66% whereas in higher age group population is
38.23%.
ER positivity of male breast carcinoma is 96%,(Figure -2) which is quite high as compared to 44% of the same
on female comparable population(Figure -3) leading us to conclude that breast carcinoma is more hormone
dependent in males as compared to females. Dual Hormone receptor negative tumors constitute 46% of the
cases of female breast cancer (Figure -4). In a developing country like India and state like Bihar where finance
and resources are major constraints, patients knowing the costly therapeutic option based on her-2 receptor
expression rarely opt for its testing. In patients below 35 years this proportion still higher constitutes 50%
(Figure -5).
Discussion
Amongst all the cancers presenting in our hospital, breast cancer constitutes the most commonly presented
variety of cancer among female patients, however in males, breast cancer is rare and constituted 1.6%, which is
slightly higher as compared to other studies, in which it accounts for only 0.7% in the study of Jemal et al [10]
,˂1% according to Giordano et al [11] and 1% in Fentiman et al study [12] of all breast cancer diagnoses. In
Korea, Male Breast Cancer constitutes 0.4 - 0.6% of all breast cancers [13]. In Europe, approximately 1% of all
Breast Cancer occurs in males, but the incidence is pretty higher in sub-Saharan Africa with 15%. This
difference in propensity for development of male breast cancer in different geographical regions may be due to
genetic, hormonal, dietary or environmental factors [14]
In U.S. the mean age at diagnosis for men with breast cancer is 67 years, which is 5 years older than the
average age at diagnosis for women. Which is close to our finding of mean age of 60.96 ± 2.46 years so just like
female breast cancer cases, in male breast cancers also age of occurrence of disease is low in India as compared
to western population. Hormone receptor expression in male breast cancer cases is quite high (96%) just like
most of the studies reporting from different parts of world [15]. Median age at diagnosis in Korea is 56 Years
[16] but in India the median age at diagnosis was 57 years (range 45-75) [17].
Mir et al found in their study that 12% breast cancer occur in women between 20-34 yrs [18] similar to our
study in which we found 15% breast cancer occurs in women between 18-35 yrs. Both ER and PR negative
tumors were highest (50%) in women of below 35 years.
Like most other studies from India our study also found the largest number of cases falling in 41-50 year age
group however it was followed by 31-40 year unlike most other studies. Most other studies have found 51-60
years as the second most common decade for breast cancer [19].
In our study, the overall ER positivity in female breast cancer cases is found to be 44.0%, which lies in the range
reported by different Indian institutes, however pretty low as compared to the reporting’s form western world
[20]. ER negative and PR positive tumors are relatively rare cancers based on hormone receptor expression
which accounts for just 1-4% [21] of all cases according to Navani et al and was found to be 5.3% [22] in the
study of Vettuparambil et al. Studies done in India and in Indian emigrants have found ER positivity in Indian
women in the range of 34.5% to 55.1% [23] The average ER positivity for white women in the US is 77% .
PR positivity from our study in female breast cancer cases is 45% which is close to percentage of ER value and
comparable to other studies reported from different parts of India with PR expression of 33.3% [24],
41.5%,
[25] and 42% [26] Though white women in US showed 55% PR positivity.
Though De Maeyer et al have completely defied ER negative and PR positive tumors in their study after
repeating the test process and putting the threshold for ER positivity as any nuclear staining of invasive tumor
cells [27]. Shen et al in their study analyzed 5374 consecutive breast cancer cases and concluded ER negative
PR positive as a definite subset group of breast cancer cases constituting 2.3% of the total number of cases [28].
Zhu et al in their study at relapse of primary to metastatic lesion in breast carcinoma found that the rate of gain
of ER and PR positivity were 10.9 and 13.5% respectively; the rates of loss of ER and PR positivity were 23.3
and 24.9%. ER and PR receptors are codependent [29]. The hormone receptors crosstalk with epidermal growth
factor receptor and may silence each other [30] Ethnic group, geographical area, genetic drift are the factors
which may influence the hormone receptor expression. In our study ER negative and PR positive tumors
constitute 9.83% which is quite high. Shen et al in their study found no survival advantage between ER
positive/PR negative and ER negative /PR positive tumors. Both of them demonstrated similar response rate to
endocrine therapy which is poorer than ER positive /PR positive.
Conclusion
Thus our study is a large study and it gives a sneak peek in the incidence of breast carcinoma in this particular
region of India and its sex wise distribution. The study also focuses on hormone receptor distribution in male
breast cancer patients, young female breast cancer patients of ˂35 yrs. and in female breast cancer patients of ˃35
yrs. We know that hormone receptor expression decides the prognosis and therapeutic options; our study throws
light on the pattern of hormone receptor expression in these geographic areas, ethnic race and in different age
groups. Cases of ER negative and PR positive breast cancer is significantly higher in this region as compared to
other studies conducted worldwide. Above facts when considered together can help in developing and deciding
the personalized treatment plan and follow up in the people of this region.
References
1. World
Health
Organization
[homepage
on
the
Internet.
The
global
burden
of
disease:2004update.http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/.
Accessed June 8, 2015.
2. Sin ghai R, Patil VW, Patil AV. Status of HER-2/5tneu receptors and Ki-67 in breast cancer of Indian
women. Int J App Basic Med Res 2011;1:15-9.
3.
Manoharan N, Tyagi BB, Raina V. Cancer incidences in rural Delhi--2004-05. Asian Pac J Cancer Prev
2006;11:73-77.
4. Murthy NS, Chaudhry K, Nadayil D, Agarwal UK, Saxena S. Changing trends in incidence of breast
cancer: Indian scenario. Indian J Cancer 2009;46:73-4.
5. Current Medical Diagnosis and Treatment. 54th ed San Francisco : Mc Graw Hill; 2015.p.720
6. Harrison’s principle of internal medicine. 19 th ed.U.S.A.: Mc Graw Hill; 2015 p. 523-4
7. Leake R. Comment. Breast. 2000;9:270.
8. Fletcher CDM. Diagnostic Histopathology of Tumors. 3rd ed. Philadelphia: Churchill Livingstone; 2007.
9. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a
prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9:R6. doi: 10.1186/bcr1639.
10. Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8–29.
11. Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann Intern Med 2002;137:678-87.
12. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet 2006; 367:595-604.
13. The Korean Breast Cancer Society. Nationwide Korean breast cancer data of 2004 using breast cancer
registration program [In Korean]. J Breast Cancer 2006;9:151-61
14. Carlsson G, Hafström L, Jönsson PE. Male breast cancer. Clin Oncol 1981;7:149-55
15. Giordano SH, Cohen DS, Buzdar AU et al. Breast carcinoma in men: a population-based study. Cancer
2004; 101:51–57.
16. Park S., Kim J.H., Koo J., Park B.W., and Lee K. S. Yonsei Med J 49(6):978 - 986, 2008
17. Chikaraddi SB, Krishnappa R, Deshmane V; Indian Journal of Cancer; 2012; 49; 3; 272-276.
18. Ruquaya Mir and V P Singh: Breast cancer in young women and its impact on reproductive function.
Apollo Medicine, September 2009:Vol. 6(3):200-208.
19. Gautham Rajan, Terence B Culas and PS Jayalakshmy World Journal of Surgical Oncology 2014, 12:120
20. SEER Stat database. [http://seer.cancer.gov/statfacts/html/breast.html
21. Kaul R, Sharma J, Minhas SS, Mardi K: Hormone receptor status of breast cancer in the Himalayan
Region of Northern India. Indian J Surg. 2011, 73: 9-12.
22. Dey S, Boffetta P, Mathews A, Brennan P, Soliman A, Mathew A: Risk factors according to estrogen
receptor status of breast cancer patients in Trivandrum, South India. Int J Cancer. 2009, 125: 1663-1670.
10.1002/ijc.24460.
23. Yip CH, Pathy NB, Uiterwaal CS, Taib NA, Tan GH, Mun KS, Choo WY, Rhodes A: Factors affecting
estrogen receptor status in a multiracial Asian country: an analysis of 3557 cases. Breast. 2011, 20 (Suppl
2): S60-S64.
24. Kuraparthy S, Reddy KM, Yadagiri LA, Yutla M, Venkata PB, Kadainti SVS, Reddy RPV: Epidemiology
and patterns of care for invasive breast carcinoma at a community hospital in Southern India. World J
Surg Oncol. 2007, 5: 56-10.1186/1477-7819-5-56
25. Rajan G., Culas T B and Jayalakshmy PS; World Journal of Surgical Oncology 2014,12:12
26. Shet T, Agrawal A, Nadkarni M, Palkar M, Havaldar R, Parmar V, Badwe R, Chinoy RF: Hormone
receptors over the last 8 years in a cancer referral center in India: what was and what is. Indian J Pathol
Microbiol. 2009, 52: 171-174.
27. De Maeyer L, Van Limbergen E, De Nys K Moerman P, Pochet N, Hendrickx W et al. Does estrogen
receptor negative/progesterone receptor positive breast carcinoma exist? J Clin Oncol. 2008; 26(2):335-6.
28. Shen Tiansheng, Brandwein-Gensler, Hameed Omar, Siegel Gene P, Wei Shi: Human Pathology 2015
Nov; 46(11):1776-84.
29. Zhu Yan-Yun, Si Wen,Ji Tie-Feng, Guo Xiao-Qin,Hu Yi, Tumor Biology June 2016, volume 37, issue
6,pg7675-7684.
30. Mirtavoos-Mahyari Hanifeh, Khosravi Adnan, Eshfahani-Monfared Zahra; Tanaffos 2014;13(1)26-34.